Antiestrogen action in the uterus: Biological ineffectiveness of nuclear bound estradiol after antiestrogen

Benita S. Katzenellenbogen, Evan R. Ferguson

Research output: Contribution to journalArticle

Abstract

These studies attempt to analyze the basis of the estrogenic and antiestrogenic action of threeà nonsteroidal clomiphene-type compounds as monitored by their ability to bind to immature rat uterine cytoplasmic estrogen receptor, transfer receptor sites to the nucleus, and elicit estrogenic responses (increased uterine weight and induction of the synthesis of a specific uterine protein, called induced protein, or “IP”), and by their ability to antagonize the effects of estradiol on these receptor interactions and uterine responses. Both CI-628 (CI) and U-11.100A (UA) [50 μg] elicit slight IP induction at 1–2 h and give pronounced uterine weight increases at 24 h but feeble increases at 72 h (3 single daily injections). Both bind to cytosol, and effect the transfer of receptor sites to the nucleus, which may account for the estrogenicity of these compounds. Both CI and UA give rapid (by 2–4 h), prolonged (for over 24 h), and complete blockage of estradiol-stimulated induction of IP synthesis. Likewise, antiestrogen treatment abolishes shortterm estradiol-stimulated uterine weight increase and antagonizes the 72 h estradiol-stimulated uterine weight response to the level attributable to the antiestrogen alone. MER-25, at the same dose (50 μg), had no estrogenic or antiestrogenic activity. Both CI and UA rapidly deplete the cytoplasmic estrogen binding capacity, reducing it to barely detectable levels for 24–42 h. Although during this eriod, no IP or uterine wet weight response can be elicited by estradiol, administration of saturating levels of [3H]estradiol in vivo or in vitro results in the appearance of considerable [3H]estradiol in the nucleus, bound to a macromolecule sedimenting identically with that of the nuclear receptorestradiol complex (5.5S) formed in the absence of prior antiestrogen exposure. Hence, the estradiol which becomes bound in the nucleus after antiestrogen is biologically ineffective. The return of IP responsiveness after antiestrogen correlates well with the level of cytoplasmic receptor capable of translocation to the nucleus, and not with the nuclear estradiol uptake capacity. Presumably, then, the antiestrogenic action of CI and UA results from their depletion of cytoplasmic receptor sites and not from their ability to block specific estradiol-nuclear receptor binding per se. These studies indicate that one should be cautious in assuming that the magnitude of an estrogen response is necessarily related to the level of estrogen receptor complex in the nucleus.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalEndocrinology
Volume97
Issue number1
DOIs
StatePublished - Jun 1975

Fingerprint

Estrogen Receptor Modulators
Uterus
Estradiol
Cytoplasmic and Nuclear Receptors
Weights and Measures
Estradiol Receptors
Estrogen Receptors
Ethamoxytriphetol
Nitromifene
Estrogens
Clomiphene
Cytosol
Proteins
Injections

ASJC Scopus subject areas

  • Endocrinology

Cite this

Antiestrogen action in the uterus : Biological ineffectiveness of nuclear bound estradiol after antiestrogen. / Katzenellenbogen, Benita S.; Ferguson, Evan R.

In: Endocrinology, Vol. 97, No. 1, 06.1975, p. 1-12.

Research output: Contribution to journalArticle

@article{87336460a77c400ba23494897cf91712,
title = "Antiestrogen action in the uterus: Biological ineffectiveness of nuclear bound estradiol after antiestrogen",
abstract = "These studies attempt to analyze the basis of the estrogenic and antiestrogenic action of three{\~A} nonsteroidal clomiphene-type compounds as monitored by their ability to bind to immature rat uterine cytoplasmic estrogen receptor, transfer receptor sites to the nucleus, and elicit estrogenic responses (increased uterine weight and induction of the synthesis of a specific uterine protein, called induced protein, or “IP”), and by their ability to antagonize the effects of estradiol on these receptor interactions and uterine responses. Both CI-628 (CI) and U-11.100A (UA) [50 μg] elicit slight IP induction at 1–2 h and give pronounced uterine weight increases at 24 h but feeble increases at 72 h (3 single daily injections). Both bind to cytosol, and effect the transfer of receptor sites to the nucleus, which may account for the estrogenicity of these compounds. Both CI and UA give rapid (by 2–4 h), prolonged (for over 24 h), and complete blockage of estradiol-stimulated induction of IP synthesis. Likewise, antiestrogen treatment abolishes shortterm estradiol-stimulated uterine weight increase and antagonizes the 72 h estradiol-stimulated uterine weight response to the level attributable to the antiestrogen alone. MER-25, at the same dose (50 μg), had no estrogenic or antiestrogenic activity. Both CI and UA rapidly deplete the cytoplasmic estrogen binding capacity, reducing it to barely detectable levels for 24–42 h. Although during this eriod, no IP or uterine wet weight response can be elicited by estradiol, administration of saturating levels of [3H]estradiol in vivo or in vitro results in the appearance of considerable [3H]estradiol in the nucleus, bound to a macromolecule sedimenting identically with that of the nuclear receptorestradiol complex (5.5S) formed in the absence of prior antiestrogen exposure. Hence, the estradiol which becomes bound in the nucleus after antiestrogen is biologically ineffective. The return of IP responsiveness after antiestrogen correlates well with the level of cytoplasmic receptor capable of translocation to the nucleus, and not with the nuclear estradiol uptake capacity. Presumably, then, the antiestrogenic action of CI and UA results from their depletion of cytoplasmic receptor sites and not from their ability to block specific estradiol-nuclear receptor binding per se. These studies indicate that one should be cautious in assuming that the magnitude of an estrogen response is necessarily related to the level of estrogen receptor complex in the nucleus.",
author = "Katzenellenbogen, {Benita S.} and Ferguson, {Evan R.}",
year = "1975",
month = "6",
doi = "10.1210/endo-97-1-1",
language = "English (US)",
volume = "97",
pages = "1--12",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "1",

}

TY - JOUR

T1 - Antiestrogen action in the uterus

T2 - Biological ineffectiveness of nuclear bound estradiol after antiestrogen

AU - Katzenellenbogen, Benita S.

AU - Ferguson, Evan R.

PY - 1975/6

Y1 - 1975/6

N2 - These studies attempt to analyze the basis of the estrogenic and antiestrogenic action of threeà nonsteroidal clomiphene-type compounds as monitored by their ability to bind to immature rat uterine cytoplasmic estrogen receptor, transfer receptor sites to the nucleus, and elicit estrogenic responses (increased uterine weight and induction of the synthesis of a specific uterine protein, called induced protein, or “IP”), and by their ability to antagonize the effects of estradiol on these receptor interactions and uterine responses. Both CI-628 (CI) and U-11.100A (UA) [50 μg] elicit slight IP induction at 1–2 h and give pronounced uterine weight increases at 24 h but feeble increases at 72 h (3 single daily injections). Both bind to cytosol, and effect the transfer of receptor sites to the nucleus, which may account for the estrogenicity of these compounds. Both CI and UA give rapid (by 2–4 h), prolonged (for over 24 h), and complete blockage of estradiol-stimulated induction of IP synthesis. Likewise, antiestrogen treatment abolishes shortterm estradiol-stimulated uterine weight increase and antagonizes the 72 h estradiol-stimulated uterine weight response to the level attributable to the antiestrogen alone. MER-25, at the same dose (50 μg), had no estrogenic or antiestrogenic activity. Both CI and UA rapidly deplete the cytoplasmic estrogen binding capacity, reducing it to barely detectable levels for 24–42 h. Although during this eriod, no IP or uterine wet weight response can be elicited by estradiol, administration of saturating levels of [3H]estradiol in vivo or in vitro results in the appearance of considerable [3H]estradiol in the nucleus, bound to a macromolecule sedimenting identically with that of the nuclear receptorestradiol complex (5.5S) formed in the absence of prior antiestrogen exposure. Hence, the estradiol which becomes bound in the nucleus after antiestrogen is biologically ineffective. The return of IP responsiveness after antiestrogen correlates well with the level of cytoplasmic receptor capable of translocation to the nucleus, and not with the nuclear estradiol uptake capacity. Presumably, then, the antiestrogenic action of CI and UA results from their depletion of cytoplasmic receptor sites and not from their ability to block specific estradiol-nuclear receptor binding per se. These studies indicate that one should be cautious in assuming that the magnitude of an estrogen response is necessarily related to the level of estrogen receptor complex in the nucleus.

AB - These studies attempt to analyze the basis of the estrogenic and antiestrogenic action of threeà nonsteroidal clomiphene-type compounds as monitored by their ability to bind to immature rat uterine cytoplasmic estrogen receptor, transfer receptor sites to the nucleus, and elicit estrogenic responses (increased uterine weight and induction of the synthesis of a specific uterine protein, called induced protein, or “IP”), and by their ability to antagonize the effects of estradiol on these receptor interactions and uterine responses. Both CI-628 (CI) and U-11.100A (UA) [50 μg] elicit slight IP induction at 1–2 h and give pronounced uterine weight increases at 24 h but feeble increases at 72 h (3 single daily injections). Both bind to cytosol, and effect the transfer of receptor sites to the nucleus, which may account for the estrogenicity of these compounds. Both CI and UA give rapid (by 2–4 h), prolonged (for over 24 h), and complete blockage of estradiol-stimulated induction of IP synthesis. Likewise, antiestrogen treatment abolishes shortterm estradiol-stimulated uterine weight increase and antagonizes the 72 h estradiol-stimulated uterine weight response to the level attributable to the antiestrogen alone. MER-25, at the same dose (50 μg), had no estrogenic or antiestrogenic activity. Both CI and UA rapidly deplete the cytoplasmic estrogen binding capacity, reducing it to barely detectable levels for 24–42 h. Although during this eriod, no IP or uterine wet weight response can be elicited by estradiol, administration of saturating levels of [3H]estradiol in vivo or in vitro results in the appearance of considerable [3H]estradiol in the nucleus, bound to a macromolecule sedimenting identically with that of the nuclear receptorestradiol complex (5.5S) formed in the absence of prior antiestrogen exposure. Hence, the estradiol which becomes bound in the nucleus after antiestrogen is biologically ineffective. The return of IP responsiveness after antiestrogen correlates well with the level of cytoplasmic receptor capable of translocation to the nucleus, and not with the nuclear estradiol uptake capacity. Presumably, then, the antiestrogenic action of CI and UA results from their depletion of cytoplasmic receptor sites and not from their ability to block specific estradiol-nuclear receptor binding per se. These studies indicate that one should be cautious in assuming that the magnitude of an estrogen response is necessarily related to the level of estrogen receptor complex in the nucleus.

UR - http://www.scopus.com/inward/record.url?scp=0016769752&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0016769752&partnerID=8YFLogxK

U2 - 10.1210/endo-97-1-1

DO - 10.1210/endo-97-1-1

M3 - Article

C2 - 166821

AN - SCOPUS:0016769752

VL - 97

SP - 1

EP - 12

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 1

ER -